Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH2:15])[CH2:8][C:7]=2[CH:6]=1)=[O:4].[F:16][C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1.[OH:27][NH2:28].[OH-].[K+]>ClCCl>[OH:27][NH:28][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH:15][S:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=3)(=[O:25])=[O:24])[CH2:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CC(N)CC2
Reactant: NO
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NO)c1ccc2c(c1)CC(NS(=O)(=O)c1cccc(F)c1)CC2

Procedure:
The title compound was prepared in two steps according to Scheme 6 by (1) treating amine VII with 3-fluorobenzenesulfonyl chloride and TEA in dichloromethane, and (2) treating the ester intermediate with aqueous HONH2 and KOH. MS: calc'd (MH+) 365, exp (MH+) 365.4. 1H NMR (CD3OD, 400 MHz), 7.75 (d, 1H, J=8.0 Hz), 7.60-7.66 (m, 2H), 7.46 (d, 1H, J=8.0 Hz), 7.41 (m, 1H), 7.36 (s, 1H), 7.14 (d, 1H, J=8.0 Hz), 3.55 (m, 1H), 2.95 (m, 2H), 2.82 (m, 1H), 2.69 (m, 1H), 1.95 (m, 1H) 1.73 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([C:25]([O:29][N:30]1N=NC2C=CC=N[C:31]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:13](=[O:15])[N:30]([O:29][CH3:25])[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](C(=O)O)C1CCCCC1)OCc1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H](NC(=O)OCc1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of (R)-benzyloxycarbonylamino-cyclohexyl-acetic acid (25 g, 88 mmol) in DMF (100 mL) at −10° C. was added HATU (36.7 g, 96 mmol, 1.0 equiv) followed by N,O-dimethyl hydroxyamine HCl salt (10.3 g, 105 mmol, 1.2 equiv). To this solution was then slowly added N-methyl morpholine (28.9 mL, 263 mmol, 3.0 equiv). The internal temperature was carefully monitored. During the addition, the internal temperature rose to 0° C. The solution was stirred at 0° C. for 2 hours after which the solution was diluted with EtOAc (500 mL) and washed with sat. aq. NaHCO3 solution, water, 1.0 N aq. HCl solution and brine. The organic layer was dried over Na2SO4 and the solvent including DMF was removed under vacuum. The residue was diluted with EtOAc and the solution was washed with water, brine, dried (MgSO4) and concentrated to give product [(R)-Cyclohexyl-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid benzyl ester 26 g (yield 90%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].CC1(C)COB([C:30]2[CH:31]=[CH:32][C:33]([F:38])=[C:34]([CH:37]=2)[C:35]#[N:36])OC1>>[F:38][C:33]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])=[CH:37][C:34]=1[C:35]#[N:36]
Reactant: CC1(C)COB(c2ccc(F)c(C#N)c2)OC1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(F)c(C#N)c4)c3)cnc2c1F
Yield: 5 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorobenzonitrile were coupled in the same way as in Example 30 to give 4,2′-difluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-3-carbonitrile as an off-white solid (9 mg, 5%): m/z (ES+) 408 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[CH2:8][C:9]2=O)=[CH:5][C:4]=1[O:15][CH2:16][C:17]#[CH:18].[CH3:19][CH2:20][O:21][C:22]([CH2:24][C:25]#[N:26])=[O:23].N1CCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C(C)=CC=CC=1.O>[CH2:20]([O:21][C:22](=[O:23])[C:24]([C:25]#[N:26])=[C:9]1[C:10]2[C:6](=[CH:5][C:4]([O:15][CH2:16][C:17]#[CH:18])=[C:3]([O:2][CH3:1])[CH:11]=2)[C:7]([CH3:14])([CH3:13])[CH2:8]1)[CH3:19]
Reactant: C#CCOc1cc2c(cc1OC)C(=O)CC2(C)C
Reactant: CCOC(=O)CC#N
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: O
Solvent: C1CCNC1
Product: C#CCOc1cc2c(cc1OC)C(=C(C#N)C(=O)OCC)CC2(C)C
Yield: 20.6 %

Procedure:
The above 6-methoxy-3,3-dimethyl-5-prop-2-ynyloxy-indan-1-one (2.44 g) was treated with 1.13 g of ethyl cyano acetate in the presence of 0.1 equivalents of pyrrolidine and benzoic acid in 20 ml of xylene. The reaction mixture was refluxed for 30 hours with simultaneous separation of water. Then, the cold reaction mixture was washed with water, concentrated and chromatographed in hexane/ethyl acetate through SiO2 to yield 0.7 g of yellow crystals. m.p. 132-136° C. UV 362 nm (ε=23′222), MS: 339(M+), 324, 300 (100%).
Reaction SMILES: [C:1]([C@@:4]1([OH:17])[C@H:12]([O:13][CH3:14])[C@H:11]([O:15][CH3:16])[CH2:10][O:9][C@:5]1([OH:8])[CH2:6][OH:7])([CH3:3])=[CH2:2].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1.C(OCC)C.CCCCC>[C:24]1([CH3:25])[CH:26]=[CH:27][C:21]([S:18]([CH:6]([C@:5]2([O:9][CH2:10][C@@H:11]([O:15][CH3:16])[C@@H:12]([O:13][CH3:14])[C@@:4]2([C:1]([CH3:3])=[CH2:2])[OH:17])[OH:8])[OH:7])(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=C(C)[C@@]1(O)[C@H](OC)[C@H](OC)CO[C@]1(O)CO
Solvent: CCOCC
Solvent: CCCCC
Solvent: c1ccncc1
Product: C=C(C)[C@@]1(O)[C@H](OC)[C@H](OC)CO[C@]1(O)C(O)S(=O)(=O)c1ccc(C)cc1
Yield: 70.8 %

Procedure:
Following the procedure described for the preparation of Example 10, starting from 0.80 g (3.22 mmol) of the compound obtained in Example 29 and 1.53 g of tosyl chloride in 15 ml of anhydrous pyridine, then purification by chromatography on silica gel (eluant: diethyl ether/pentane, 2:1), 0.92 g (2.28 mmol) of the desired product in the form of a white-coloured foam is obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:20].O.CC(O)=O>CC#N>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][OH:20])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(C(=O)CO)ccc1OCCCCl
Yield: 32.8 %

Procedure:
A solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 g, 17.7 mmol), [bis(trifluoroacetoxy)iodo]benzene (15.6 g, 36.2 mmol), H2O (18 ml), CH3CO2H (2.8 ml) and CH3CN (90 ml) was refluxed for 3 hours. The CH3CN was removed under reduced pressure and the resulting yellow liquid was partitioned between H2O and CH2Cl2. The biphasic mixture was filtered, the organic phase collected, washed with saturated NaHCO3 solution and concentrated to afford 1.5 g of an amorphous brown solid. The solid was flash chromatographed on silica gel, eluting the column with 5% EtOAc/CH2Cl2. Concentration of similar fractions afforded 0.7 g of the compound as a pale yellow solid, m.p. 99°-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([I:29])[CH:27]=2)[N:22]=[CH:21][N:20]=1.CC(O)(C)C>ClCCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([I:29])[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: Clc1ncnc2ccc(I)cc12
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: Cl
Product: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2Cl)c1
Yield: 116.7 %

Procedure:
3-Chloro-4-(3-fluoro-benzyloxy)-phenylamine (3.1 g, 12 mmol) and 4-chloro-6-iodo-quinazoline (3.28 g, 11.3 mmol) are dissolved in a 1:1 mixture of DCE:t-BuOH (56 ml). The reaction mixture is refluxed for 19 hours. The product is isolated by suction filtration through sintered glass, washed with excess DCM, and air dried to afford 3.8 g (7.0 mmol, 58%) of the clean desired material.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][OH:13].CNC.Cl>[Cu].CCOCC.O>[CH3:12][O:13][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: [Cu]
Agent: CNC
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: COc1cc(Cl)ccc1C(=O)O

Procedure:
A mixture of 2,4-dichlorobenzoic acid (67.4 g), absolute methanol (135 ml), and copper powder (3.37 g) is refluxed for 6-7 hours while introducing gaseous dimethylamine. The reaction mixture is mixed with a large amount of water, acidified with hydrochloric acid, and shaken with ether. The organic layer is washed with water, dried over sodium sulfate, and evaporated to remove the solvent. The residue is washed with isopropyl ether and filtered to give 2-methoxy-4-chlorobenzoic acid (43.6 g) as crystals melting at 139.5° to 141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=O)[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:25]([O-:28])([O-])=O.[K+].[K+].CN([CH:34]=[O:35])C>C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:25](=[O:28])[N:15]([CH2:14][C@@H:34]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:35])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=c1n(C[C@H](O)c2cccc(Cl)c2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 60 °C
Yield: 52 %

Procedure:
To a stirred solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (20 mg, 0.06 mmol) prepared as described in Example 1, in 0.25 mL of DMF was added R-(+)-3-chlorostyrene oxide (0.007 mL, 0.06 mmol) and 15 mg of K2CO3. The resulting red solution was heated to 60° C. for 19 h and, upon cooling to RT, the mixture was diluted with 5 mL of ethyl acetate and 5 mL of 1N HCl. The layers were separated, and the organic layer was washed with 5 mL of saturated aqueous NaCl. The organic layer was dried over MgSO4, filtered and evaporated to give a yellow oil. The material was purified using reverse-phase HPLC to give the title compound, (R)-7,8-bis(4-chlorophenyl)-2-(2-(3-chlorophenyl)-2-hydroxyethyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (15 mg, 52% yield) as a yellow solid. HRMS Anal. Calc'd for C25H17Cl3N4O2, 510.04, [M+H]+=511.0509 observed. 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.16 (s, 1H), 7.15-7.05 (m, 9H), 6.92 (d, 2H, J=8.6 Hz), 5.05-4.95 (m, 1H), 4.13-4.08 (m, 2H), 1.55 (br s, 1H).
Reaction SMILES: [N+:1](C1NC2C=CC=CC=2N=1)([O-])=O.CCCCCC.CCOC(C)=O.[CH2:25]([N:28]1[C:32]2[CH:33]=[C:34](N)[CH:35]=[CH:36][C:31]=2[N:30]=[CH:29]1)[CH2:26][CH3:27]>CO.[Pd]>[CH2:25]([N:28]1[C:32]2[CH:33]=[CH:34][C:35]([NH2:1])=[CH:36][C:31]=2[N:30]=[CH:29]1)[CH2:26][CH3:27]
Reactant: O=[N+]([O-])c1nc2ccccc2[nH]1
Reactant: CCCn1cnc2ccc(N)cc21
Agent: [Pd]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCn1cnc2cc(N)ccc21

Procedure:
A solution of 5-nitrobenzimidazole (3.6 g, 23 mmol) in 100 ml of THF was stirred with NaH (1.5 g, 33 mmol) for 0.5 h at 25° C. To the solution was added allyl bromide (4.8 ml, 57 mmol) and resulting mixture was stirred for 12 h. The reaction mixture was concentrated in vacuo to provide an oil, which was subjected to column chromatography to yield 4.0 g (19.7 mmol, 89%) of a mixture of 1- and 3-allyl-5-nitrobenzimidazole. The nitrobenzimidazole mixture was stirred in 100 ml of MeOH for 12 under H2 in the presence of 10% Pd/C. The reaction mixture was filtered and concentrated in vacuo to provide oily residue which was subjected to column chromatography (50% Hexane/EtOAc) to provide 1.2 g (7.0 mmol) of 1-propyl-5-aminobenzimidazole and 1.1 9 (6.4 mmol) of 3-propyl-5-aminobenzimidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.NO.[ClH:13].C([O-])([O-])=O.[K+].[K+].[CH3:20][C:21]#[N:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:22][C:21]2[CH:4]=[CH:3][C:2]([Cl:13])=[CH:7][CH:20]=2)=[CH:4][CH:3]=1
Reactant: Cl
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC#N
Agent: NO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc(Nc2ccc(Cl)cc2)cc1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
Under air, a 500-mL rbf was charged with (4-chlorophenyl)boronic acid (15.0 g, 96.0 mmol, 1 eq.), NH2OH.HCl (8.0 g, 115 mmol, 1.2 eq.), CuBr (2.75 g, 19.18 mmol, 0.2 eq.), K2CO3 (19.89 g, 144.0 mmol, 1.5 eq.), and CH3CN (320 mL). The reaction mixture was stirred at 70° C. for 24 h. The completion of the reaction was monitored by TLC. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on a silica gel using 10%-20% EtOAc in hexanes to give the product as brown oil that solidifies when dried under vacuum.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C)C=O.[O-]CC.[Na+].[CH:31]1([CH2:34]Br)[CH2:33][CH2:32]1>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH2:34][CH:31]3[CH2:33][CH2:32]3)[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: BrCC1CC1
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ccccc12
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c(=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione and 30 ml of dimethylformamide was added 1.4 g of sodium ethoxide, and the whole was stirred for 30 minutes at room temperature. To this was further added 4.1 g of cyclopropylmethyl bromide, and the mixture was reacted for 2 hours at room temperature. Then, the solvent was distilled off from the resulting mixture under reduced pressure to leave a residue, to which was added water to precipitate a crude product. Recrystallization of this product from methanol gave 3.1 g of 1-(m-nitrophenyl)-3-cyclopropylmethyl-quinazoline- 2,4(1H, 3H)-dione as colorless needles, melting, at 163°-164° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:12](=[O:23])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1.Br[CH2:25][CH2:26][CH2:27][Cl:28]>CN(C)C=O>[Cl:28][CH2:27][CH2:26][CH2:25][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:23])[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:4]1=[O:3]
Reactant: ClCCCBr
Reactant: COc1ccc(Cn2c(=O)[nH]c3ccccc3c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3ccccc3n(CCCCl)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.34 g) in N,N-dimethylformamide (30 ml), 2,4-dioxo-3-(4-methoxybenzyl)-1,2,3,4-tetrahydroquinazoline (2.0 g) obtained in Reference Example 26 was added, and the mixture was stirred at room temperature for 30 minutes. To this mixture, 1-bromo-3-chloropropane (1.05 ml) was added and the mixture was stirred for further 13.5 hours. The solvent was distilled off under reduced pressure, and the residue was combined with iN hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried (Na2SO4), and the solvent was distilled off under reduced pressure. The residue was subjected to a column chromatography on a silica gel eluting with n-hexane-ethyl acetate (5:1, v/v) to give the title compound (1.58 g, 62%). Recrystallization from ethyl acetate-isopropyl ether yielded a colorless crystal having a melting point of 124 to 125° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14](OCC)=[O:15])=[C:10]1[C:19]([O:21]CC)=O.O.[NH2:25][NH2:26]>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[C:19](=[O:21])[NH:25][NH:26][C:14](=[O:15])[C:11]=2[CH:12]=[CH:13]1
Reactant: NN
Reactant: CCOC(=O)c1ccn(-c2ccc(C)cc2C)c1C(=O)OCC
Solvent: O
Solvent: CCO
Product: Cc1ccc(-n2ccc3c(=O)[nH][nH]c(=O)c32)c(C)c1
Yield: 88.7 %

Procedure:
To a solution of diethyl 1-(2,4-dimethylphenyl)-1H-pyrrole-2,3-dicarboxylate (0.5 g, 1.59 mmol) in ethanol (5 ml) was added hydrazine monohydrate (0.38 ml, 7.93 mmol) and the mixture was heated under reflux for 14 hours. During the reaction, additional hydrazine monohydrate (0.2 ml×3) was added to the mixture. The solvent was removed in vacuo and the residue was treated with 2N hydrochloric acid at 80° C. for 20 min. After cooling, crystals were collected by filtration, washed with water and dried to give 0.36 g (89%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2].[CH3:25][C:26]([CH3:30])(O)[C:27]#[N:28].[O:31]1[CH2:36]CC(=O)C[CH2:32]1>CN(C)C(=O)C.ClCCl.O>[F:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][N:13]([C:26]4([C:27]#[N:28])[CH2:30][CH2:36][O:31][CH2:32][CH2:25]4)[CH2:14][CH2:15]3)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1F)oc(=O)n2C1CCNCC1
Reactant: O=C1CCOCC1
Reactant: CC(C)(O)C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc2c(cc1F)oc(=O)n2C1CCN(C2(C#N)CCOCC2)CC1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 207.1 %

Procedure:
6-Fluoro-5-methyl-3-(4-piperidinyl)-1,3-benzoxazol-2(3H)-one (D3, 318 mg, 0.915 mmol) was dissolved in N,N-dimethylacetamide (10 mL) at rt under argon. Magnesium sulfate (562 mg, 4.67 mmol), acetone cyanohydrin (0.17 mL, 1.86 mmol) and tetrahydro-4H-pyran-4-one (0.17 mL, 1.84 mmol) were added and the reaction was heated at 70° C. for 24 h under a gentle stream of argon. The mixture was then cooled to rt, diluted with 1:1 dichloromethane:water (30 mL) and sonicated for 20 min. The phases were allowed to separate and the organic phase was dried by filtering through a hydrostatic cartridge. A further 10 mL of dichloromethane was added to the aqueous phase and the mixture stirred vigorously for 10 min. The 2 phases were again separated and the organic phase was dried by filtering through a hydrostatic cartridge. The combined organic layers were concentrated by rotary evaporation to give 4-[4-(6-fluoro-5-methyl-2-oxo-1,3-benzoxazol-3(2H)-yl)-1-piperidinyl]tetrahydro-2H-pyran-4-carbonitrile (D4, 681 mg, 45% purity, 93% yield) as an orange solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([NH:9][C:10](=[O:21])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19]O)[CH2:14][CH2:13]2)=[C:7]([S:22][CH3:23])[CH:6]=[C:5]([CH3:24])[N:4]=1.[CH2:25]([O:32][C:33]1[CH:42]=[CH:41][C:36]2[N:37]=[C:38]([SH:40])[NH:39][C:35]=2[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:25]([O:32][C:33]1[CH:42]=[CH:41][C:36]2[N:37]=[C:38]([S:40][CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][N:12]([CH2:11][C:10]([NH:9][C:8]4[C:3]([S:2][CH3:1])=[N:4][C:5]([CH3:24])=[CH:6][C:7]=4[S:22][CH3:23])=[O:21])[CH2:13][CH2:14]3)[NH:39][C:35]=2[CH:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Reactant: Sc1nc2ccc(OCc3ccccc3)cc2[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccc(OCc4ccccc4)cc3[nH]2)CC1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
Under argon, N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide (1.00 g, 2.70 mmol), 5-benzyloxy-2-mercaptobenzimidazole (2.57 g, 10.0 mmol), and triphenylphosphine (2.50 g, 9.53 mmol) were dissolved in N,N-dimethylformamide (30 mL). To the solution, under cooling with ice, diethyl azodicarboxylate (1.27 mL, 8.07 mmol) was added dropwise, followed by stirring for one hour at the same temperature. Ethyl acetate and 1 mol/L hydrochloric acid were added to the reaction mixture. The aqueous layer was separated from the mixture, and the organic layer was further extracted with 1 mol/L hydrochloric acid. The obtained aqueous layers were combined and adjusted to basic conditions with a 1 mol/L aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was removed under reduced pressure. The thus-obtained residue was purified through silica gel column chromatography (chloroform : saturated ammonia-methanol=20:1), to thereby yield 1.56 g of 2-[4-[2-(5-benzyloxybenzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide as a colorless amorphous product (yield 94.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[Cl:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:53][O:54][C:55]1[CH:62]=[CH:61][C:58]([CH2:59]O)=[CH:57][CH:56]=1>C1COCC1>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH2:59][C:58]2[CH:61]=[CH:62][C:55]([O:54][CH3:53])=[CH:56][CH:57]=2)=[O:19])[C:3]=1[Cl:21]
Reactant: COc1ccc(CO)cc1
Reactant: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)O)n2)c1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)c2nc(-c3ccc(Cl)c(OC)c3F)cc(N)c2Cl)cc1
Reaction time: 48 h
Yield: 20.8 %

Procedure:
To a solution of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid (600 mg, 1.81 mmol) in THF (10 mL) was added triphenylphosphine (475 mg, 1.81 mmol), diethyl azodicarboxylate (0.29 mL, 1.81 mmol), and 4-methoxybenzyl alcohol (0.34 mL, 2.72 mmol). The reaction mixture was stirred for 48 h. Additional triphenylphosphine (475 mg, 1.81 mmol) was added to the reaction, and the reaction mixture was stirred for 24 h. The reaction mixture was concentrated to dryness and was purified by silica gel chromatography (eluting with a 0-100% EtOAc/hexane gradient) to provide an off-white solid (170 mg, 26%): mp 73-83° C.; 1H NMR (400 MHz, CDCl3) δ 7.66 (dd, J=8.6, 7.8 Hz, 1H), 7.45-7.38 (m, 2H), 7.22 (dd, J=8.7, 1.8 Hz, 1H), 7.16 (d, J=1.7 Hz, 1H), 6.94-6.87 (m, 2H), 5.38 (s, 2H), 4.80 (s, 2H), 3.96 (d, J=0.8 Hz, 3H), 3.81 (s, 3H); ESIMS m/z 451 ([M+H]+), 449 ([M−H]−).
Reaction SMILES: CC(C)[C@H](N1CC2C(=CC(C3C=CC(NC(C4SC(C5C=CC=CC=5)=CN=4)=O)=CC=3)=CC=2)C1=O)C(OC)=O.[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:54]=[C:53]3[C:49]([CH2:50][N:51]([C@@H:56]([CH:61]([CH3:63])[CH3:62])[C:57]([O:59][CH3:60])=[O:58])[C:52]3=[O:55])=[CH:48][CH:47]=2)=[CH:42][CH:41]=1.[C:64]1([C:70]2[NH:71][C:72]([C:75](OCC)=[O:76])=[N:73][N:74]=2)[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>>[CH3:62][CH:61]([CH3:63])[C@H:56]([N:51]1[CH2:50][C:49]2[C:53](=[CH:54][C:46]([C:43]3[CH:42]=[CH:41][C:40]([NH:39][C:75]([C:72]4[NH:71][C:70]([C:64]5[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=5)=[N:74][N:73]=4)=[O:76])=[CH:45][CH:44]=3)=[CH:47][CH:48]=2)[C:52]1=[O:55])[C:57]([O:59][CH3:60])=[O:58]
Reactant: CCOC(=O)c1nnc(-c2ccccc2)[nH]1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4nnc(-c5ccccc5)[nH]4)cc3)cc2C1=O

Procedure:
The compound of example 628 was prepared analogous to the compound of example 611 by reaction of compound of example 6 with ethyl 5-phenyl-4H-1,2,4-triazole-3-carboxylate.